Vitamin D, Parathyroid Hormone and the Metabolic Syndrome in Middle

European Journal of Endocrinology (2009) 161 947–954 ISSN 0804-4643

CLINICAL STUDY Vitamin D, parathyroid hormone and the metabolic syndrome in middle-aged and older European men David M Lee, Martin K Rutter1, Terence W O’Neill, Steven Boonen2, Dirk Vanderschueren3, Roger Bouillon4, Gyorgy Bartfai5, Felipe F Casanueva6,7, Joseph D Finn, Gianni Forti8, Aleksander Giwercman9, Thang S Han10, Ilpo T Huhtaniemi11, Krzysztof Kula12, Michael E J Lean13, Neil Pendleton14, Margus Punab15, Alan J Silman, Frederick C W Wu16 and the European Male Ageing Study Group ARC Epidemiology Unit, The University of Manchester, Manchester M13 9PT, UK, 1Manchester Diabetes Centre, The University of Manchester, Manchester, UK, 2Division of Gerontology and Geriatrics and Centre for Musculoskeletal Research, Department of Experimental Medicine, 3Department of Andrology and Endocrinology and 4Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium, 5Department of Obstetrics, Gynaecology and Andrology, Albert Szent-Gyorgy Medical University, Szeged, Hungary, 6Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela, Spain, 7CIBER de Fisiopatologıá Obesidad y Nutricioń (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain, 8Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy, 9Reproductive Medicine Centre, Malmo¨ University Hospital, University of Lund, Malmo¨, Sweden, 10Department of Endocrinology, Royal Free and University College Hospital Medical School, Royal Free Hospital, Hampstead, London, UK, 11Department of Reproductive Biology, Imperial College London, Hammersmith Campus, London, UK, 12Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland, 13Department of Human Nutrition, University of Glasgow, Glasgow, UK, 14Clinical Gerontology, The University of Manchester, Hope Hospital, Salford, UK, 15Andrology Unit, United Laboratories of Tartu University Clinics, Tartu, Estonia and 16Department of Endocrinology, Manchester Royal Infirmary, The University of Manchester, Manchester, UK (Correspondence should be addressed to D M Lee; Email: [email protected])

Abstract Objectives: Low serum 25-hydroxyvitamin D (25(OH)D) and elevated parathyroid hormone (PTH) levels have been linked to insulin resistance, the metabolic syndrome (MetS) and its components. Data in healthy, community-dwelling Europeans are lacking, and previous studies have not excluded subjects receiving drug treatments that may distort the relationship between 25(OH)D/PTH and MetS. The aim of our analysis was to examine the association of 25(OH)D and PTH with Adult Treatment Panel III-defined MetS in middle-aged and older European men. Design: This was a population-based, cross-sectional study of 3369 men aged 40–79 years enrolled in the European Male Ageing Study. Results: After exclusion of subjects with missing data, 3069 men with a mean (GS.D.) age of 60G11 years were included in the analysis. Age-adjusted 25(OH)D levels were inversely associated with waist circumference, systolic blood pressure (BP), triglycerides, and glucose (all P!0.01). Age-adjusted PTH levels were only associated with waist and diastolic BP (both P!0.05). After adjusting for age, centre, season and lifestyle factors the odds for MetS decreased across increasing 25(OH)D quintiles (odds ratios 0.48 (95% confidence intervals 0.36–0.64) highest versus lowest quintile; Ptrend!0.001). This relationship was unchanged after adjustment for PTH, but was attenuated after additional adjustment for homoeostasis model assessment of insulin resistance (0.60 (0.47–0.78); Ptrend!0.001). There was no association between PTH and MetS. Conclusions: Our results demonstrate an inverse relationship between 25(OH)D levels and MetS, which is independent of several confounders and PTH. The relationship is partly explained by insulin resistance. The clinical significance of these observations warrants further study.

European Journal of Endocrinology 161 947–954

Introduction related to prevalent metabolic syndrome (MetS) (4), whereas US population-based data from NHANES, in 25-Hydroxyvitamin D (25(OH)D) and parathyroid which vitamin D levels were lower, indicated a marked hormone (PTH) are important physiological regulators inverse relationship between these variables (5). Both of extracellular calcium homoeostasis. A number of studies also suggested that PTH was related to prevalent recent population-based, cross-sectional studies suggest MetS in older men. There is some biological plausibility additional metabolic roles for these hormones (1–5). for these relationships because low vitamin D levels, Data from the California-based Rancho Bernardo study, and to a lesser extent elevated PTH levels, have been in which subjects have high sunlight exposure and associated with glucose intolerance and insulin resist- high vitamin D levels, indicated that 25(OH)D was not ance (6–10).

q 2009 European Society of Endocrinology DOI: 10.1530/EJE-09-0496 Online version via www.eje-online.org

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Although the studies by Reis (4, 5) and others (3, 11) 500I automated sphygmomanometer (Omron Health- were population based and some were adjusted for care Ltd, Milton Keynes, UK). Height was measured several confounders including PTH and 25(OH)D levels, barefoot to the nearest 1 mm using a stadiometer subjects taking anti-hypertensive and lipid-lowering (Leicester Height Measure, SECA UK Ltd, Birmingham, medications were not excluded from these analyses. UK), and weight to the nearest 0.1 kg using an electronic We are not aware of any previous studies that have scale (SECA, model no. 8801321009, SECA UK Ltd) with specifically explored the effects of these groups of drugs subjects wearing light clothing. Each centre’s electronic on the relationship between the vitamin D/PTH axis scales and stadiometers were calibrated on a monthly and MetS, though it is possible that any associations basis. Waist circumference was measured thrice to the may potentially be distorted by medication use targeting nearest 1 mm using anthropometric tape, mid-way component parts of the MetS. between the lowest rib and the iliac crest with the The purpose of our study was to examine the cross- subject standing, and the median used to score. Current sectional associations of 25(OH)D and PTH levels with prescription and non-prescription drug use was recorded MetS in a large population-based cohort of European with participants bringing in all medications for men and to contrast the strength of any associations confirmation. after excluding those taking medications that might influence these relationships. Biochemistry Phlebotomy was performed prior to 1000 h to obtain a Methods fasting blood sample from all subjects. Processed serum K Subjects was stored and protected from light at 80 8C prior to analysis and shipped on dry ice to central laboratories The European Male Ageing Study (EMAS) is a prospective, for measurement of 25(OH)D (Katholieke Universiteit non-interventional cohort studyof male ageing in Europe. Leuven) and PTH (University of Santiago de Compos- Details regarding recruitment, response rates and assess- tela). Serum 25(OH)D levels were determined using RIA ments have been previously described (12). Briefly, non- (RIA kit: DiaSorin, Stillwater, MN, USA). Intra- and institutionalised men aged 40–79 years were recruited inter-assay coefficients of variation (CV) for 25(OH)D from municipal or population registers in eight centres: were 11 and 8% respectively. The detection limit of the Florence (Italy); Leuven (Belgium); Lodz (Poland); Malmo¨ RIA kit was 5.0 nmol/l 25(OH)D. Serum was assayed for (Sweden); Manchester (UK); Santiago de Compostela PTH using a chemiluminescence immunoassay (Nichols (Spain); Szeged (Hungary); Tartu (Estonia). For the Advantage Bio-Intact PTH assay, Quest Diagnostics, baseline survey, stratified random sampling was used Madison, NJ, USA). Intra- and inter-assay CV for PTH with the aim of recruiting equal numbers of men into each were 6 and 2.8% respectively. The detection limit of the of four age bands (40–49, 50–59, 60–69 and 70–79 chemiluminescence immunoassay was 0.16 pmol/l. years). Subjects were invited by letter to complete a short Analyses for cholesterol, high-density lipoprotein postal questionnaire and to attend for screening at a local (HDL) cholesterol and triglycerides were performed clinic. The mean adjusted response rate across the eight locally in all centres using commercially available centres was 43% (range 24–60%). The study was funded enzymatic methods. Fasting glucose was measured by the European Union, and ethical approval for the study using standard hexokinase enzymatic assays. Insulin was obtained in accordance with local institutional was assayed using quimioluminiscence (University of requirements in each centre. Santiago de Compostela). Insulin resistance was calcu- lated using the homoeostasis model assessment of insulin resistance (HOMA-IR) (14). All clinical path- Assessments ology laboratories were accredited by the relevant The postal questionnaire included items concerning national authorities and adhered to current guidelines demographic, health and lifestyle information. on Good Laboratory Practice as specified by EU Directive Subjects were asked about tobacco use (response 2004/9/EC (15). setZcurrent/past/non-smoker) and typical alcohol consumption during the preceding month (response Metabolic syndrome setZeveryday/5–6 days/week/3–4 days/week/1–2 days/ week/! once/week/not at all). Those who agreed to To assess the prevalence of MetS among the EMAS participate subsequently attended a research clinic to cohort, we used the current ATPIII guidelines (16). The complete an interviewer-assisted questionnaire (IAQ) ATPIII definition of MetS was met if subjects had at least and physiological assessments. The IAQ included the three of the following: a waist circumference O102 cm, physical activity scale for the elderly (PASE) (13) to a triglyceride level R1.7 mmol/l, a HDL cholesterol level assess physical activity levels. Blood pressure measure- !1.03 mmol/l, systolic blood pressure R130 mmHg ments were performed after a 5-min rest period to the and/or diastolic blood pressure R85 mmHg, and nearest 1 mmHg with subjects seated using an Omron fasting glucose R5.6 mmol/l.

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Analysis Table 1 Baseline characteristics (nZ3069).

Statistical analyses were performed using Intercooled Variable Mean (S.D.) Stata version 9.2 (StataCorp., College Station, TX, USA). Subjects with missing 25(OH)D and PTH measurements Age (years) 60.0 (11.0) Z Z Waist circumference (cm) 98.4 (10.9) (n 151), or incomplete MetS data (n 149) were Systolic blood pressure (mmHg) 146 (21) excluded, leaving 3069 men in the main analysis. Diastolic blood pressure (mmHg) 87 (12) 25(OH)D and PTH were examined as continuous HDL cholesterol (mmol/l) 1.4 (0.4) variables or classified into quintiles. Age, the PASE Triglycerides (mmol/l) 1.6 (1.1) score and individual components of the MetS were Glucose (mmol/l) 5.6 (1.4) Body mass index (kg/m2) 27.6 (4.1) treated as continuous variables in linear regression 25(OH)D (nmol/l) 62.3 (31.3) models. Season of attendance at the clinic was defined Parathyroid hormone (pmol/l) 3.1 (1.5) as winter (January–March), spring (April–June), summer Physical activity scale for the elderly 195 (92) (July–September) and autumn (October–December). % The associations of 25(OH)D and PTH with covariates were ATPIII metabolic syndrome 31.7 O examined using Pearson correlation and one-way ANOVA. Waist circumference 102 cm 33.6 Blood pressure R130/85 mmHga 84.9 We initially explored the association of both 25(OH)D HDL cholesterol !1.03 mmol/l 12.9 and PTH levels with MetS components using linear Triglycerides R1.7 mmol/l 30.3 regression (adjusting for age), with results expressed as b Glucose R5.6 mmol/lb 36.0 c coefficients and 95% confidence intervals (CI). Mean levels Diabetes 7.6 G Current smoker 21.1 ( S.E.M.) of each MetS component by quintile of either Alcohol consumption (R1 day/week) 56.2 25(OH)D or PTH were then estimated using multiple Lipid-lowering medicationd 13.0 linear regression models adjusting for potential confounders (age, physical activityand season). In addition, to aMeasured blood pressure and/or using anti-hypertensive drugs. bMeasured blood glucose and/or using anti-diabetic drugs. allow for the likelihood that observations are independent cSelf-report and/or using anti-diabetic drugs. across centres, but not necessarily within centres, robust dIncludes fibrate derivatives, bile acid sequestrants, niacin and HMG-CoA standard errors were requested using Stata’s cluster reductase inhibitors. subcommand with centre as the clustering variable. Higher levels of PTH were observed in the winter Linear trends were assessed by using the quintiles of (3.2G1.7 pmol/l) as opposed to the summer months 25(OH)D or PTH as ordinal terms in the regression model. (2.9G1.5 pmol/l), and these seasonal differences were Finally, multivariable logistic regression models assessed statistically significant (PZ0.03). PTH levels increased the individual and combined associations of 25(OH)D and with age (rZ0.13, P!0.001), BMI (rZ0.08, PTH with MetS after serial adjustments for potential P!0.001) and were inversely related to PASE score confounders, including HOMA-IR, with results expressed (rZK0.13, P!0.001). Current smokers had lower as odds ratios (ORs) and 95% CI. Effect modification by age levels of both 25(OH)D and PTH than non-smokers was also assessed by inclusion of interaction terms (P!0.01). Subjects reporting drinking one or more between 25(OH)D or PTH concentration and age (by alcoholic drinks per week had higher 25(OH)D and decade) in the logistic regression models. lower PTH levels than those drinking less frequently (both P!0.01). As with 25(OH)D, mean levels of PTH varied between centres ranging from 2.7 pmol/l in Results Szeged to 3.4 pmol/l in Leuven (adjusted for season, P!0.001). Using linear regression, we did not find a Subjects significant association between the latitude of each The clinical characteristics of the 3069 men included in centre, which ranged from 42.888N(Santiago)to the analysis sample are shown in Table 1. 58.388N (Tartu), and either 25(OH) (bZK0.10, PZ0.3) or PTH (bZK0.01, PZ0.1) after adjusting for season of attendance. 25(OH)D and PTH 25(OH)D was inversely related to PTH (rZK0.18, Metabolic syndrome P!0.001) and varied markedly by season of measurement (meanGS.D.): summer, 85G33 versus winter, The MetS was present in just under one-third of subjects 50G26 nmol/l (P!0.001). 25(OH)D was inversely (Table 1). Among those not using anti-hypertensive, relatedtobodymassindex(BMI)(rZK0.10, diabetes and/or lipid-lowering medications, this fell P!0.001), and positively related to PASE score to one quarter (24.7%). The prevalence of individual (rZ0.10, P!0.001). There were significant between- MetS components according to the current ATPIII centre differences in mean levels of 25(OH)D, ranging guidelines ranged from 13% of subjects with low from 77 nmol/l in Malmo¨to47nmol/linTartu HDL cholesterol to 85% of subjects with hypertension. (adjusted for season, P!0.001). Age-adjusted associations between 25(OH)D and PTH

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Table 2 Age-adjusted associations between 25-hydroxyvitamin D (25(OH)D) or parathyroid hormone (PTH) and components of the metabolic syndrome: linear regressions.

Independent variables

25(OH)D – (per 10 nmol/l) PTH – (per pmol/l) Dependent variables b Coefﬁcients (95% CI)a

Waist circumference (cm) K0.413 (K0.536, K0.291)* 0.596 (0.344, 0.847)* Systolic blood pressure (mmHg) K0.548 (K0.773, K0.323)* 0.406 (K0.058, 0.870)* Diastolic blood pressure (mmHg) K0.214 (K0.354, K0.075)* 0.525 (0.238, 0.811)* HDL cholesterol (mmol/l) 0.006 (0.002, 0.010)* K0.009 (K0.017, K0.001)* Triglycerides (mmol/l) K0.037 (K0.050, K0.025)* K0.008 (K0.033, 0.018)* Glucose (mmol/l) K0.032 (K0.048, K0.016)* K0.019 (K0.052, 0.013)*

*P!0.05. Note: although the distribution of triglycerides was positively skewed, using log-transformed triglycerides in the above regressions did not change the significance of the associations. aAdjusted for age. and components of the MetS are presented in Table 2. Table 3. Waist circumference, systolic blood pressure, Increasing 25(OH)D levels were associated with triglycerides and glucose levels were inversely lower values for waist circumference, systolic blood associated with increasing 25(OH)D quintiles (all pressure, diastolic blood pressure, triglycerides and Ptrend%0.05), and these relationships were essentially glucose, and higher values for HDL cholesterol. unchanged after additional adjustment for smoking, However, increasing levels of PTH were only signi- alcohol consumption and other MetS components ficantly associated with higher values for waist (all Ptrend!0.05, data not shown). Increasing PTH circumference and diastolic blood pressure, and lower quintiles were positively related to waist circumference, values for HDL cholesterol. When the regressions of systolic blood pressure and diastolic blood pressure 25(OH)D and PTH versus blood pressure, lipids and (all Ptrend%0.02), and these trends remained significant glucose were additionally adjusted for waist circumfer- for waist circumference and diastolic blood pressure ence, the associations between 25(OH)D and both (both Ptrend!0.02) after additional adjustment for diastolic blood pressure and HDL cholesterol, and PTH smoking, alcohol consumption and other MetS com- and HDL cholesterol was no longer significant (all ponents, but not for systolic blood pressure (PtrendZ0.6, PO0.07; data not shown). data not shown). Adjusted means for individual components of The associations of 25(OH)D or PTH with MetS are MetS across 25(OH)D or PTH quintiles are shown in summarised in Table 4. The adjusted odds for MetS

Table 3 Adjusted means (S.E.M.) for components of the metabolic syndrome versus quintiles of 25(OH)D and PTH.

Quintiles of 25(OH)D (range nmol/l) nZ617 nZ620 nZ615 nZ610 nZ607

Dependent variable I(!35.7) II (35.7–49.4) III (49.5–65.1) IV (65.2–85.9) V (O85.9) Ptrend Waist circumference (cm) 99.2 (0.7) 99.3 (0.7) 99.0 (0.7) 98.2 (1.0) 96.0 (1.1) 0.05 Systolic blood pressure (mmHg) 148.1 (2.2) 146.4 (2.4) 145.6 (1.9) 145.7 (1.5) 142.8 (1.4) 0.05 Diastolic blood pressure (mmHg) 87.9 (1.5) 87.5 (1.6) 87.4 (1.6) 86.9 (1.1) 86.1 (0.7) 0.3 HDL cholesterol (mmol/l) 1.40 (0.04) 1.38 (0.05) 1.40 (0.03) 1.39 (0.05) 1.46 (0.06) 0.4 Triglycerides (mmol/l) 1.73 (0.08) 1.65 (0.13) 1.58 (0.09) 1.54 (0.10) 1.30 (0.06) 0.001 Glucose (mmol/l) 5.84 (0.12) 5.70 (0.11) 5.61 (0.13) 5.63 (0.10) 5.48 (0.10) 0.002

Quintiles of PTH (range pmol/l) nZ614 nZ614 nZ614 nZ614 nZ613

I(!2.01) II (2.01–2.55) III (2.56–3.10) IV (3.11–3.86) V (O3.86)

Waist circumference (cm) 97.6 (0.7) 98.0 (0.9) 97.9 (0.9) 98.9 (0.7) 99.5 (0.8) 0.02 Systolic blood pressure (mmHg) 145.3 (2.1) 144.7 (2.0) 145.6 (1.6) 145.1 (2.0) 148.0 (2.0) 0.05 Diastolic blood pressure (mmHg) 86.3 (1.4) 86.5 (1.3) 86.5 (1.0) 87.6 (1.2) 88.8 (1.5) 0.004 HDL cholesterol (mmol/l) 1.41 (0.05) 1.41 (0.05) 1.43 (0.05) 1.40 (0.04) 1.38 (0.04) 0.3 Triglycerides (mmol/l) 1.66 (0.14) 1.61 (0.10) 1.49 (0.09) 1.53 (0.07) 1.53 (0.05) 0.2 Glucose (mmol/l) 5.84 (0.13) 5.68 (0.17) 5.61 (0.11) 5.51 (0.07) 5.63 (0.06) 0.1

Values shown are means (S.E.M.). Adjusted for age, physical activity, season and centre. 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone. Note: although the distribution of triglycerides was positively skewed, using log-transformed triglycerides in the above regressions, Ptrend, remained unchanged.

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Table 4 Adjusted odds ratios (95% conﬁdence intervals) for the association of 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) with the metabolic syndrome.

Quintiles of 25(OH)D (range nmol/l)

I(!35.7) II (35.7–49.4) III (49.5–65.1) IV (65.2–85.9) V (O85.9) Ptrend Mean 25(OH)D (nmol/l) 26.2 42.7 57.2 74.5 111.9 Model 1 1.00 (referent) 0.97 (0.65–1.43) 0.75 (0.51–1.10) 0.63 (0.39–1.01) 0.48 (0.36–0.64) !0.001 Model 2 1.00 (referent) 0.96 (0.65–1.41) 0.75 (0.50–1.11) 0.62 (0.40–0.97) 0.47 (0.37–0.62) !0.001 Model 3 1.00 (referent) 0.94 (0.62–1.43) 0.78 (0.56–1.08) 0.61 (0.36–1.04) 0.60 (0.47–0.78) !0.001

Quintiles of PTH (range pmol/l)

I(!2.01) II (2.01–2.55) III (2.56–3.10) IV (3.11–3.86) V (O3.86) Ptrend Mean PTH (pmol/l) 1.59 2.29 2.81 3.46 5.22 Model 1 1.00 (referent) 0.92 (0.66–1.26) 0.77 (0.50–1.19) 0.88 (0.59–1.31) 0.95 (0.59–1.55) 0.8 Model 2 1.00 (referent) 0.88 (0.65–1.20) 0.72 (0.47–1.11) 0.80 (0.55–1.18) 0.82 (0.51–1.33) 0.4 Model 3 1.00 (referent) 0.97 (0.72–1.32) 0.86 (0.55–1.35) 1.03 (0.84–1.26) 0.98 (0.71–1.36) 0.9

Model 1: adjusted for age, smoking, alcohol consumption, physical activity, season and centre. Model 2: adjusted for all variables in Model 1 plus PTH in 25(OH)D analysis and 25(OH)D in PTH analysis. Model 3: adjusted for all variables in Model 2 plus HOMA-IR. Note: there was no evidence that age modified the relationship between either 25(OH)D or PTH and the metabolic syndrome in any of the models (PinteractionO0.1 in all cases). decreased by more than 50% across increasing quintiles MetS components. Waist circumference, systolic blood of 25(OH)D (Model 1), and this relationship was pressure, triglycerides and glucose levels were inversely unchanged after adjustment for PTH (Model 2), but associated with 25(OH)D after additional adjustment was attenuated (w20%) after additional adjustment for for physical activity, season and centre. The odds of HOMA-IR (Model 3). There was a significant linear MetS decreased w50% across increasing 25(OH)D trend across 25(OH)D quintiles for each model quintiles, and this relationship was in part explained (Table 4), primarily driven by the significant OR in the by insulin resistance. Waist circumference, diastolic highest quintile. There was no evidence that the blood pressure and systolic blood pressure were association of 25(OH)D with MetS differed by age associated with PTH levels after multivariable adjust- decade (PinteractionO0.1). No association between PTH ment, but there was no evidence of an association and MetS was observed in any of the models, and there between PTH levels and MetS. was no evidence that the PTH–MetS association was modified by age (PinteractionO0.1). When the above logistic regression models were Previous studies of 25(OH)D and MetS repeated following exclusion of subjects receiving Several factors might explain why population-based diabetes, anti-hypertensive and/or lipid-lowering studies exploring the association of 25(OH)D with Z medications (n 1960), the results were broadly MetS, and its components have yielded conflicting unchanged. In Model 1, the adjusted odds for MetS results. Ford and co-workers showed in NHANES w decreased 40% across increasing quintiles of subjects that the adjusted risk for MetS was inversely 25(OH)D (OR 0.56 (95% CI 0.33, 0.94) for highest associated with 25(OH)D levels, but this study was Z versus lowest quintile; Ptrend 0.01). The association limited by the failure to adjust for PTH (1). This is was unchanged following adjustment for PTH (Model 2) potentially important because low calcium and vitamin (0.57 (0.35, 0.93) for highest versus lowest quintile; Z D levels are physiological stimuli for PTH synthesis, Ptrend 0.01), but additional adjustment for HOMA- and there is evidence that elevated PTH may influence IR (Model 3) again attenuated the relationship the risk for MetS (17–24). In a subsequent analysis (0.70 (0.47, 1.04) for highest versus lowest quintile; Z that adjusted for PTH levels, Reis and co-workers found Ptrend 0.04). As with the analysis using the entire no association between MetS with 25(OH)D levels sample, we observed no relationship between PTH in men or women (4). These Rancho Bernado study and MetS in models excluding men using specific participants resided in southern California where medications (all P O0.3, data not shown). trend high levels of exposure to u.v. radiation probably contributed to the relatively high 25(OH)D levels (mean w105 nmol/l). In a separate study in NHANES Discussion subjects, Reis and co-workers reported a strong Main findings inverse relationship between 25(OH)D levels and prevalent MetS that was independent of PTH levels In this population-based study of middle-aged and and other important confounders (5).Themean older European men, we showed that age-adjusted 25(OH)D level among this representative sample 25(OH)D levels were significantly associated with all of the non-institutionalised US population was

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Downloaded from Bioscientifica.com at 09/29/2021 03:46:31AM via free access 952 D M Lee and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 w62 nmol/l. These findings were in stark contrast therefore, that a threshold also exists for PTH whereby to those of the Rancho Bernardo study and suggested elevated PTH may influence the development of MetS that a threshold may exist whereby vitamin D whereas lower levels do not. In either case, our data do deficiency may influence incident MetS (5), whereas not support an independent association between the higher levels may not (4). Our results and mean MetS and PTH in men. 25(OH)D levels (62 nmol/l) are very similar to Reis’ recent NHANES study (5) and, therefore, lend some support to the threshold hypothesis. The different Strengths and limitations 25(OH)D levels reported in the Rancho Bernado study (4) and the NHANES study (5) should be We have studied a large, population-based sample of interpreted cautiously, however, as different assays European men. We adjusted for physical activity, were used to measure 25(OH)D. Whether the relation- 25(OH)D and PTH status which were assessed by ships observed are explained by variation in sun standardised methods (12) and the age-stratified exposure is uncertain and our results did not change enrolment facilitated robust exploration of age following additional adjustment for latitude – a interactions. To allow for possible distortion of the surrogate measure of sun exposure (data not shown). relationship between the vitamin D/PTH axis and MetS The mechanism(s) by which low vitamin D could by medication use targeting diabetes, hypertension be associated with MetS remain speculative (5). Data or dyslipidaemia, we repeated our logistic regression in humans suggest that low 25(OH)D levels are models excluding subjects who were currently treated associated with glucose intolerance and insulin resist- for pre-existing components of the MetS. Although ance (6, 9, 10). In support of this, we showed that our rationale to exclude these men was theoretical, it the relationship between MetS and 25(OH)D was in part was based on the premise that the association between explained by insulin resistance. The cross-sectional 25(OH)D/PTH and MetS may be falsely inflated nature of our data does not exclude the possibility if subjects with currently treated components of the that obesity and hypertension, and associated MetS were included in the analysis. Evidence of a co-morbid conditions, could reduce levels of outdoor stronger relationship between 25(OH)D and the MetS in physical activity and sun exposure. This explanation analyses using the entire EMAS sample supports this may be less likely because even short duration sun notion, although the overall pattern of associations exposure from late spring to early autumn will stimulate was unchanged. vitamin D synthesis and when we additionally excluded Our study has a number of limitations. The cross- many of our less healthy subjects who were receiving sectional design limits conclusions about causal therapy for diabetes, hypertension and/or dyslipidae- relationships. We enrolled non-institutionalised, mia, our results were largely unchanged. Residual primarily Caucasian men with a study response rate confounding from low 25(OH)D levels acting as of 43%, which could limit the generalisability to other a marker for a less healthy lifestyle and diet not groups. 25(OH)D and PTH were assayed from a single identified by the measured covariates might also measurement and, consequently, the strength of the explain our findings. observed associations are likely to be conservative. However, given that the prevalence of MetS in our sample was relatively common and we used a logistic Previous studies of PTH and MetS regression model to determine ORs from cross-sectional data, it is possible that we may have overestimated the In the Rancho Bernardo study and in NHANES subjects, magnitude of the observed associations (25). Finally, we Reis and co-workers showed that prevalent MetS was did not adjust for calcium intake, although adjustment positively related to PTH concentration among older for PTH in the 25(OH)D analysis should partly men but not women (4, 5). In contrast, we found no compensate for this. relationship between MetS and PTH levels in men and no evidence of an age interaction even in minimally O adjusted models (Pinteraction 0.1). It is possible that Clinical implications when we excluded men who were using medications targeting component parts of the MetS, our data reflect Studies in animals (26–28) and some (29, 30) but not the true physiology more closely. However, we found no all (31) data in humans suggest that vitamin D therapy evidence of an association between PTH and MetS even could improve glucose intolerance and insulin resist- when subjects receiving diabetes, anti-hypertensive ance (29). These studies and the data presented here and/or lipid-lowering medications were excluded from could inform therapeutic trials of vitamin D on incident the analysis. MetS and ultimately on incident diabetes and/or Our mean PTH levels (3 pmol/lz28 pg/ml) were cardiovascular disease in subjects with low 25(OH)D lower than compared with Reis’ studies; 51 pg/ml (4) levels. However, it is premature to suggest vitamin D and 42 pg/ml (5) respectively, and it is possible, therapy to prevent MetS, diabetes or cardiovascular

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Downloaded from Bioscientifica.com at 09/29/2021 03:46:31AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 Vitamin D, PTH and metabolic syndrome in men 953 disease particularly since the relationship between 5 Reis JP, von Muhlen D & Miller ER III. Relation of 25-hydro- 25(OH)D and cardiovascular risk may be non-linear xyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults. European Journal of Endocrinology and possibly U-shaped (32). 2008 159 41–48. 6 Chiu KC, Chu A, Go VL & Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. American Journal of Clinical Nutrition 2004 79 820–825. Conclusion 7 Chiu KC, Chuang LM, Lee NP, Ryu JM, McGullam JL, Tsai GP & Saad MF.Insulin sensitivity is inversely correlated with plasma intact We have shown that in a population-based study of parathyroid hormone level. Metabolism 2000 49 1501–1505. European men, low 25(OH)D levels were linked to 8 Norman AW, Frankel JB, Heldt AM & Grodsky GM. Vitamin D prevalent MetS and that this relationship was partially deficiency inhibits pancreatic secretion of insulin. Science 1980 mediated by insulin resistance. In contrast to previous 209 823–825. studies, PTH levels were not associated with MetS. 9 Liu E, Meigs JB, Pittas AG, McKeown NM, Economos CD, Booth SL & Jacques PF. Plasma 25-hydroxyvitamin D is associated with Further prospective studies are needed to ascertain the markers of the insulin resistant phenotype in nondiabetic adults. relationship between vitamin D and MetS. Journal of Nutrition 2009 139 329–334. 10 Forouhi NG, Luan J, Cooper A, Boucher BJ & Wareham NJ. Baseline serum 25-hydroxy vitamin D is predictive of future glycemic Declaration of interest status and insulin resistance: the Medical Research Council Ely The authors have no financial arrangements or conflict of interest to Prospective Study 1990–2000. Diabetes 2008 57 2619–2625. disclose concerning this manuscript. 11 Hypponen E, Boucher BJ, Berry DJ & Power C. 25-Hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross- sectional study in the 1958 British Birth Cohort. Diabetes 2008 57 Funding 298–305. 12 Lee DM, O’Neill TW, Pye SR, Silman AJ, Finn JD, Pendleton N, The European Male Ageing Study is funded by the Commission of the Tajar A, Bartfai G, Casanueva F, Forti G, Giwercman A, European Communities Fifth Framework Program ‘Quality of Life and Huhtaniemi IT, Kula K, Punab M, Boonen S, Vanderschueren D & Management of Living Resources’ Grant QLK6-CT-2001-00258. Wu FC. The European Male Ageing Study (EMAS): design, methods Additional support was also provided by the Arthritis Research and recruitment. International Journal of Andrology 2009 32 11–24. Campaign (UK). 13 Washburn RA, Smith KW, Jette AM & Janney CA. The physical activity scale for the elderly (PASE): development and evaluation. Journal of Clinical Epidemiology 1993 46 153–162. Acknowledgements 14 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF & Turner RC. Homeostasis model assessment: insulin resistance and The EMAS study group: Florence (Gianni Forti, Luisa Petrone, Antonio beta-cell function from fasting plasma glucose and insulin Cilotti); Leuven (Dirk Vanderschueren, Steven Boonen, Herman Borghs); Lodz (Krzysztof Kula, Jolanta Slowikowska-Hilczer, Renata concentrations in man. Diabetologia 1985 28 412–419. Walczak-Jedrzejowska); London (Ilpo Huhtaniemi); Malmo¨ (Alek- 15 Directive 2004/9/EC of the European Parliament and of the sander Giwercman); Manchester (Frederick Wu, Alan Silman, Neil Council on the inspection and verification of good laboratory Pendleton, Terence O’Neill, Joseph Finn, Philip Steer, Abdelouahid practice (GLP) 2004. Tajar, David Lee, Stephen Pye); Santiago (Felipe Casanueva, Mary 16 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Lage); Szeged (Gyorgy Bartfai, Imre Fo¨ldesi, Imre Fejes); Tartu (Margus Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Punab, Paul Korrovitz); Turku (Min Jiang). The authors wish to Spertus JA & Costa F. Diagnosis and management of the metabolic thank the men who participated in the eight countries, the syndrome: an American Heart Association/National Heart, Lung, research/nursing staff in the eight centres: C Pott, Manchester; and Blood Institute Scientific Statement. Circulation 2005 112 E Wouters, Leuven; M Nilsson, Malmo¨; M del Mar Fernandez, Santiago 2735–2752. de Compostela; M Jedrzejowska, Lodz; H-M Tabo, Tartu; A Heredi, 17 Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ & Shaw S. 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